The lung is a major portal of entry to environmental pollutants including pesticides. This complex organ is now recognized as more than simply a route of exposure and organ for gas exchange but one with noteworthy capabilities for metabolism of inhaled xenobiotics. Since the toxicity of many chemicals is directly related to the activation or detoxification by various enzyme systems, the ability of the lung to biotransform these chemicals is highly relevant for assessing potential toxicity from inhaled pollutants. The purpose of this project is to characterize the interactions between the lung and two anticholinesterase insecticides, carbofuran and parathion. Specifically, this project will attempt to accomplish, 5 specific aims. Specific Aim 1 will establish in vitro metabolism and pharmacokinetics of carbofuran and parathion in the isolated perfused lung and in vitro microsomal enzyme assays. Specific Aim 2 will establish in vitro toxicity of carbofuran and parathion by measuring lung acetylcholinesterase inhibition and selected lung function parameters. Specific Aim 3 will establish in vivo deposition and clearance of inhaled carbofuran and parathion aerosols using a nose-only inhalation facility. Pharmacokinetics, metabolism and acetylcholinesterase inhibition will be evaluated in lung and blood. Specific Aim 4 will establish in vivo effects of carbofuran and parathion on selected lung function parameters. Using data obtained from these studies, Specific Aim 5 will be the development of a physiologically-based pharmacokinetic model of inhaled pesticide aerosol-lung interactions. Such a model can serve as a prototype for other chemical aerosol-lung interactions where metabolism is related to toxicity and will assist extrapolations of animal data to human exposures.